Urokinase separated and purified from urine or cultured kidney cells and streptokinase recovered from streptococci are nowadays practically used as plasminogen activators. Specifically, these plasminogen activators are used as thrombolytic agents.
However, it is known that these plasminogen activators are often administered to patients in large amounts in order to obtain necessary therapeutic effects overcoming their poorness in affinity with fibrin and thus cause side effects such as internal hemorrhage. Specifically, plasmin which is produced in circulating blood by these plasminogen activators tends to lose activity immediately upon combination with plasmin inhibitors in the blood. Accordingly, in order to exhibit the necessary therapeutic effects, these plasminogen activators must be administered in large amounts to produce plasmin, viz., in an amount exceeding that of the plasmin inhibitors in the blood. However, the production of a large amount of plasmin will decompose fibrinogen, resulting in hemorrhage. Accordingly, if a plasminogen activator which has a high affinity with fibrin and is capable of producing plasmin on fibrin can be obtained, it becomes possible to decompose fibrin with a small amount of the plasminogen activator without being subjected to the influence of plasmin inhibitors in circulating blood, and also to reduce the effects of decomposing fibrinogen. Therefore, it has been desired to provide a thrombolytic agent having a high affinity for fibrin which shows a high thrombolytic activity using a small amount thereof, and which has less side effects.
One of the inventors, with others, has already found a novel plasminogen activator having properties listed below in a culture liquid of normal diploid cells of human bodies and endeavored to put it in practical use (European patent application (OPI) No. 0100982).
(a) molecular weight: 63,000.+-.10,000 PA0 (b) isoelectric point: 7.0 to 8.5 PA0 (c) affinity to fibrin: present PA0 (d) affinity to Concanavalin A: present PA0 (e) optimum pH: 7.0 to 9.5 PA0 (f) no reactivity with anti-urokinase specific antibody.
However, because of low productivity, this plasminogen activator has been difficult to provide in large amounts on an industrial scale.